Challenges in implementing individualized medicine illustrated by antimetabolite therapy of childhood acute lymphoblastic leukemia

Predicting the response to medical therapy and subsequently individualizing the treatment to increase efficacy or reduce toxicity has been a longstanding clinical goal. Not least within oncology, where many patients fail to be cured, and others are treated to or beyond the limit of acceptable toxicity, an individualized therapeutic approach is indicated. The mapping of the human genome and technological developments in DNA sequencing, gene expression profiling, and proteomics have raised the expectations for implementing genotype-phenotype data into the clinical decision process, but also multiplied the complex interaction of genetic and other laboratory parameters that can be used for therapy adjustments. Thus, with the advances in the laboratory techniques, post laboratory issues have become major obstacles for treatment individualization. Many of these challenges have been illustrated by studies involving childhood acute lymphoblastic leukemia (ALL), where each patient may receive up to 13 different anticancer agents over a period of 2-3 years. The challenges include i) addressing important, but low-frequency outcomes, ii) difficulties in interpreting the impact of single drug or single gene response data that often vary across treatment protocols, iii) combining disease and host genomics with outcome variations, and iv) physicians' reluctance in implementing potentially useful genotype and phenotype data into clinical practice, since unjustified downward or upward dose adjustments could increase the of risk of relapse or life-threatening complications. In this review we use childhood ALL therapy as a model and discuss these issues, and how they may be addressed.